Mutations in <i>COQ2</i> in Familial and Sporadic Multiple-System Atrophy

Mitsui, Jun; Matsukawa, Takashi; Ishiura, Hiroyuki; Fukuda, Yoko; Ichikawa, Yaeko; Date, Hidetoshi; Ahsan, Budrul; Nakahara, Yukiko; Momose, Yoshika; Takahashi, Yūji; Iwata, Atsushi; Goto, Jun; Yamamoto, Yorihiro; Komata, Makiko; Shirahige, Katsuhiko; Hara, Kenju; Kakita, Akiyoshi; Yamada, Mitsunori; Takahashi, Hitoshi; Onodera, Osamu; Nishizawa, Masatoyo; Takashima, Hiroshi; Kuwano, Ryozo; Watanabe, Haruo; Ito, Mizuki; Sobue, Gen; Soma, Hiroyuki; Yabe, Ichiro; Sasaki, Hidenao; Akiyama, Masashi; Ishikawa, Kinya; Mizusawa, Hidehiro; Kanai, Kazuaki; Hattori, Takamichi; Kuwabara, Satoshi; Arai, Kimihito; Koyano, Shigeru; Kuroiwa, Yoshihiro; Hasegawa, Kazuko; Yuasa, Tatsuhiko; Yasui, Kenichi; Nakashima, Kenichiro; Ito, Hidetaka; Izumi, Yuishin; Kaji, Ryuji; Kato, Takeshi; Kusunoki, Susumu; Osaki, Yasushi; Horiuchi, Masahiro; Kondo, Tomoyoshi; Murayama, Shigeo; Hattori, Nobutaka; Yamamoto, Mitsutoshi; Matsushima, Miho; Satake, Wataru; Toda, Tatsushi; Dürr, Alexandra; Brice, Alexis; Filla, Alessandro; Klockgether, Thomas; Wallner, Ullrich; Nicholson, Garth A.; Gilman, Sid; Shults, Clifford W.; Tanner, Caroline M.; Kukull, Walter A.; Lee, Virginia M.‐Y.; Masliah, Eliezer; Low, Phillip A.; Sandroni, Paola; Trojanowski, John Q.; Ozelius, Laurie J.; Foroud, Tatiana; Tsuji, Shoji

doi:10.1056/nejmoa1212115

Cited by 304 publications

(166 citation statements)

References 35 publications

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“…We analyzed the SCA1 , SCA2 , SCA3 , SCA6 , SCA7 , SCA8 , SCA12 , SCA17 , SCA31 , DRPLA , and COQ2 genes in all patients with MSA-C and in a part of patients with SCA3 [1,16]. The remaining part of patients with SCA3 had been genetically diagnosed in other hospitals.…”

Section: Methodsmentioning

confidence: 99%

Differential Progression of Dysphagia in Heredity and Sporadic Ataxias Involving Multiple Systems

et al. 2015

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Sporadic ataxia affecting multiple systems, such as cerebellar, extrapyramidal, and autonomic systems, is known as multiple system atrophy cerebellar type (MSA-C), while similar multisystem involvements are seen in certain types of hereditary ataxia, such as spinocerebellar ataxia type 3 (SCA3). Dysphagia is a common symptom that can predispose to aspiration pneumonia, a major cause of death in patients with these diseases. Although the progressions of dysphagia in patients with MSA-C have been reported sporadically, those in SCA3 have not been reported. We retrospectively compared the results of repetitive videofluoroscopic examinations in patients with SCA3 (n = 6) and in those with MSA-C (n = 7). The result showed that the gross progression of dysphagia was significantly slower in patients with SCA3 than in those with MSA-C, but the maximum progression speeds were not significantly different. The dysphagia severities were not associated with impaired activity of daily living evaluated by the Barthel index in MSA-C, but were associated in SCA3. Despite the small number of patients enrolled, these data suggest that physicians should monitor swallowing functions in patients with SCA3 after mild dysphagia develops because it may progress as rapidly as it does in MSA-C.

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Section: Methodsmentioning

confidence: 99%

Differential Progression of Dysphagia in Heredity and Sporadic Ataxias Involving Multiple Systems

et al. 2015

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“…We also performed Southern blot analysis at Columbia University research laboratory to determine the size of hexanucleotide repeat expansions of C9orf72 and found that both the proband and her brother had repeats of more than 1000 with similar expansion size. In addition, we also excluded the COQ2 sequence variant V343A associated with MSA 12 and the pathological repeat expansions of SCA36 13 in the proband.…”

Section: Introductionmentioning

confidence: 99%

Multiple System Atrophy and Amyotrophic Lateral Sclerosis in a Family With Hexanucleotide Repeat Expansions inC9orf72

et al. 2014

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“…This indicates that abnormal mitochondrial accumulation, as well as fission, possibly precedes GCI formation. The Multiple System Atrophy Research Consortium reported that functionally impairing nucleotide variants in COQ2 , which encodes the protein coenzyme Q 2 that is essential for the biosynthesis of coenzyme Q 10 , were associated with an increased risk of MSA in multiplex families and in about 10% of sporadic MSA cases [23]. Patients with defective COQ2 mutations were shown to have GCI-positive oligodendroglia [23], providing direct evidence for a role of mitochondrial dysfunction in MSA pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…We studied patients with sporadic MSA (Cases 1–10, 12–14), familial MSA (Case 11), who was already reported as homozygously carrying the M128V-V393A COQ2 mutation [22,23], normal controls who died from non-neurological conditions (Cases 15–26), and disease controls including ALS (Cases 27 and 28), oligodendroglioma (Cases 29 and 30), MS (Cases 31–34) and others (Cases 35–37) (Table 1). The Case 11 as well as her/his sibling were both clinically diagnosed as MSA-P, pathologically confirmed as MSA (22), and whole genome sequence analysis on them lead to an identification of COQ2 mutations in MSA (23).One of these two sibs, the only available sample upon investigation, were confirmed to show a significantly reduced intracellular coenzyme Q10 level in her/his brain tissue, suggesting a functional consequence of this mutation (23).…”

Section: Methodsmentioning

confidence: 99%

Relocation of p25α/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy

Ota

Obayashi

Ozaki

et al. 2014

acta neuropathol commun

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p25α/tubulin polymerization promoting protein (TPPP) is an oligodendroglial protein that plays crucial roles including myelination, and the stabilization of microtubules. In multiple system atrophy (MSA), TPPP is suggested to relocate from the myelin sheath to the oligodendroglial cell body, before the formation of glial cytoplasmic inclusions (GCIs), the pathologic hallmark of MSA. However, much is left unknown about the re-distribution of TPPP in MSA. We generated new antibodies against the N- and C-terminus of TPPP, and analyzed control and MSA brains, including the brain of a familial MSA patient carrying homozygous mutations in the coenzyme Q2 gene (COQ2). In control brain tissues, TPPP was localized not only in the cytoplasmic component of the oligodendroglia including perinuclear cytoplasm and peripheral processes in the white matter, but also in the nucleus of a fraction (62.4%) of oligodendroglial cells. Immunoelectron microscopic analysis showed TPPP in the nucleus and mitochondrial membrane of normal oligodendroglia, while western blot also supported its nuclear and mitochondrial existence. In MSA, the prevalence of nuclear TPPP was 48.6% in the oligodendroglia lacking GCIs, whereas it was further decreased to 19.6% in the oligodendroglia with phosphorylated α-synuclein (pα-syn)-positive GCIs, both showing a significant decrease compared to controls (62.4%). In contrast, TPPP accumulated in the perinuclear cytoplasm where mitochondrial membrane (TOM20 and cytochrome C) and fission (DRP1) proteins were often immunoreactive. We conclude that in MSA-oligodendroglia, TPPP is reduced, not only in the peripheral cytoplasm, but also in the nucleus and relocated to the perinuclear cytoplasm.

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Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy

Cited by 304 publications

References 35 publications

Differential Progression of Dysphagia in Heredity and Sporadic Ataxias Involving Multiple Systems

Differential Progression of Dysphagia in Heredity and Sporadic Ataxias Involving Multiple Systems

Multiple System Atrophy and Amyotrophic Lateral Sclerosis in a Family With Hexanucleotide Repeat Expansions inC9orf72

Relocation of p25α/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy

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